In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 76, No. 14_Supplement ( 2016-07-15), p. 2077-2077
Abstract:
Number of active anticancer compounds failed in the drug development due to unfavorable pharmacological properties. Design of pro-drugs is plausible approach to improve drug-like properties of biologically active compounds. Betulinic acid is a well-known representative of triterpenes, which possess a moderate cytotoxic activity and high selectivity towards the tumor cells. However, its pharmacological properties, particularly solubility and bioavailability, are poor. In order to improve pharmacology of betulinic acid derivatives, we have synthesized and tested activities of above 40 carbonate based prodrugs. We have developed methods for activation of “pro-drug” derivatives of betulinic acid by primary rat hepatocytes. Cytotoxicity of pro-drugs and activated metabolites was measured on the sensitive tumor cell line CCRF-CEM (human T-lymphoblastic leukemia). We have identified 21 prodrugs & gt;10 times more cytotoxic to CCRF-CEM cells after pre-incubation with rat hepatocytes. The best candidate pro-drug showed & gt;100 fold increase of cytotoxicity due to metabolic activation and it was cytotoxic to cancer cells in sub-micromolar concentrations. Our concept and predicted mechanisms of pro-drug activation were verified by HPLC-MS/MS where the pro-drugs and corresponding active compounds were identified and quantified. For the most active derivatives we have tested ADME characteristics and in vivo pharmacokinetics which showed significantly improved drug-like properties. Analysis of anti-cancer activities of the pro-drugs is currently being performed. This work was supported by grants LF_2015_031 and by the National Sustainability Program (LO1304). Citation Format: Petr Dzubak, Renata Burianova, Martina Michalova, Barbora Liskova, Milan Urban, Jan Sarek, Adela Galandakova, Jitka Ulrichova, Marian Hajduch. Carbonate prodrugs derived from triterpenoids with high cytotoxic activity. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2077.
Type of Medium:
Online Resource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.AM2016-2077
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2016
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
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